Powder injection of the donepezil semi palmoxiric acid salt, composition containing same and preparation method therefor

ABSTRACT

A powder injection of a donepezil semi palmoxiric acid salt, a composition containing the same and a preparation method therefor. The powder injection contains donepezil semi palmoxiric acid salt crystals, and the average grain size of the crystals ranges from 0.5 μm to 100 μm.

This application claims the priority of Chinese Patent Application No.201710099184.5, filed before the CNIPA on Feb. 23, 2017, titled “powderinjection of donepezil semi pamoate for injection and preparation methodthereof”, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present disclosure pertains to the technical field of medicamentpreparation, in particular to a method for preparing a powder injectionof donepezil semi pamoate.

BACKGROUND OF THE INVENTION

Alzheimer disease (AD) has a complex pathogenesis and is a result ofmultifactorial interactions. The commonly accepted hypotheses at presentinclude: cholinergic damage hypothesis, excitatory amino acid toxicityhypothesis, amyloid β-protein (Aβ) cascade hypothesis, Tau proteinhyperphosphorylation hypothesis and oxidative stress hypothesis. The USFood and Drug Administration (FDA) currently only approves fivemedicaments for the treatment of AD, four of which areacetylcholinesterase inhibitors (AChEIs), namely, tacrine (1993),donepezil (1996), rivastigmine (2000), and galantamine (2001), andanother is an antagonist of N-methyl-D-aspartic acid (NMDA) receptor,namely memantine (2003). Among them, tacrine has been basicallyabandoned due to the requirement of 4 times administeration per day andthe potential severe hepatotoxicity. The other four medicaments arecurrently the first-line drugs for the treatment of AD, which canmoderately improve the cognitive ability, the ability of daily life,mental behavior and overall function of AD patients, and have goodsafety and tolerance. Donepezil, rivastigmine and galantamine have equalefficacy, while donepezil is superior in safety, tolerance and patientcompliance. In China, the commonly used medicaments for AD treatmentinclude: huperzine A, donepezil, piracetam, oxiracetam, pyritinol,nimodipine, citicoline, ginkgo extract, dihydroergotoxine, memantine,acetylglutamine, and idebenone, etc.

Donepezil is an effective medicament for AD treatment in both domesticand foreign markets. It has a high selectivity and a reversibletreatment of AD. However, conventional preparations require dailyadministration. The senile dementia patients have poor compliance, andthey cannot take medicine at the specified dose on time, thus seriouslyaffecting treatment effects. In order to solve the problems caused bythe conventional preparations of donepezil, domestic and foreignscholars have made various attempts on long-acting donepezilpreparations. At present, many technologies for long-acting donepezilpreparations have been disclosed, as described in patents such asUS2011/0218216, WO2010/039381, CN101167697, CN1602867, and CN103316974.However, these long-acting preparations also have problems in the highmanufacturing cost and difficulty in production on a commercial scale.There is still a need to improve the preparation process of donepezil tofully exert the efficacy of donepezil and maximize its medical benefits.

SUMMARY OF THE INVENTION

An object of the present disclosure is to provide a powder injection ofdonepezil semi pamoate, a composition containing the same and apreparation method thereof. The object of the present disclosure isrealized by the following technical solutions.

Firstly, the present disclosure provides a powder injection of donepezilsemi pamoate comprising donepezil semi pamoate crystals having anaverage particle size (D₅₀) 0.5-200 μm, or not less than 180 μm, or notless than 160 μm, or not less than 140 μm, or not less than 120 μm, ornot less than 100 μm, or not less than 80 pin, or not less than 60 μm,or not less than 30 μm, or not less than 10 μm, preferably 0.5-52 μm,more preferably 2-32 μm, and still more preferably 4-15 μm.

In some embodiments of the present disclosure, the donepezil semipamoate crystals have an angle of repose 25-46 degrees, preferably 32-43degrees.

The present disclosure provides a method for preparing a powderinjection of donepezil semi pamoate, comprising: crystallizing donepezilsemi pamoate, subjecting to a dry pulverization, optionally filling intoa sterilization container, and then subjecting to a sterilizationprocess.

In some specific embodiments of the present disclosure, the method forpreparing the powder injection of donepezil semi pamoate may comprisethe following steps:

-   -   step 1: dissolving donepezil hydrochloride in purified water,        stirrng, and filtering to obtain a filtrate;    -   step 2: dissolving disodium pamoate in purified water, stirring,        and filtering to obtain a filtrate; and    -   step 3: adding donepezil semi pamoate seed crystals to the        filtrate obtained in step 1 to obtain a solution; then dropwise        adding the filtrate obtained in step 2 into the above solution,        stirring for 1-2 hours, filtering to obtain a filter cake;        washing the filter cake with purified water, drying, and        performing a dry pulverization and a sterilization process.

The dry pulverization is selected from the group consisting of a sievepulverization, a ball milling pulverization and/or a jet pulverization.

The sterilization process in the above preparation method is a γ-rayirradiation sterilization, an electron beam irradiation sterilization ora microwave irradiation sterilization, preferably an electron beamirradiation sterilization, and an irradiation dose of the electron beamirradiation sterilization is 25 kGy to 60 kGy. The sterilizationcontainer can be made of borosilicate glass with pyrogens removed.

In some specific embodiments of the present disclosure, in particular,the dry pulverization may be performed by using a sieve pulverizerequipped with a 10-20 mesh sieve.

The present disclosure also provides a composition comprising donepezilsemi pamoate, which comprises the aforementioned powder injection ofdonepezil semi pamoate or the powder injection of donepezil semi pamoateobtained by the aforementioned method.

In some embodiments of the present disclosure, the powder injection ofdonepezil semi pamoate is present in 13%-24% by mass, based on totalmass of the composition.

In some embodiments of the present disclosure, the composition furthercomprises a diluent; preferably, based on total mass of the diluent, thediluent comprises 0.03%-3% of a suspending agent, 3%-6% of a tensionagent, and 0.03%-2% of a wetting agent by mass.

In some embodiments of the present disclosure, the suspending agent isone or more selected from the group consisting of methylcellulose,sodium carboxymethylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, alginate, chitosan, glucan, gelatin, polyethyleneglycol, polyoxyethylene ether, and polyoxypropylene ether, preferablysodium carboxymethylcellulose (CMC-Na). The tension agent is one or moreselected from the group consisting of sodium chloride, dextrose,mannitol, sorbitol, lactose, and sodium sulfate, preferably mannitol orsodium chloride. The wetting agent is one or more selected from thegroup consisting of polysorbate 80, polysorbate 20, poloxamer, lecithin,polyoxyethylene ether, polyoxypropylene ether, and sodium deoxycholate,preferably poloxamer 188 or Tween 80.

In some embodiments of the present disclosure, the suspending agent mayalso range from 0.5% to 1.5%, preferably from 0.75% to 1.5%, the wettingagent may also range from 0.05% to 0.5%, preferably from 0.05% to 0.2%,and the tension agent may also range from 4.5% to 5% or from 4.5% to 6%.

The present disclosure still further provides a method for preparing aninjection of donepezil semi pamoate, which is characterized by followingsteps:

-   -   (1) obtaining the aforementioned powder injection of donepezil        semi pamoate, or the powder injection of donepezil semi pamoate        obtained by the method of any one of the preceding embodiments;        and    -   (2) mixing the powder injection of step (1) with a diluent to        obtain an injection of donepezil semi pamoate, wherein based on        total mass of the diluent, the diluent comprises 0.03%-3% of a        suspending agent, 3%-6% of a tension agent, 0.03%-2% of a        wetting agent by mass and water for injection.

In some embodiments of the present disclosure, the suspending agent mayalso range from 0.5% to 1.5%, preferably from 0.75% to 1.5%; the wettingagent may also range from 0.05% to 0.5%, preferably from 0.05% to 0.2%;and the tension agent may also range from 4.5% to 6%. The suspendingagent is preferably CMC-Na; the tension agent is preferably mannitol orsodium chloride; and the wetting agent is preferably poloxamer 188 orTween 80.

The powder injection of donepezil semi pamoate provided in the presentdisclosure has a reduced stimulation of the medicament by controllingthe particle size of the medicament. Further, the powder injection ofdonepezil semi pamoate provided in the present disclosure has goodfluidity and is easier for dispensing. Certainly, it is not necessary toachieve all of the advantages described above when implementing any oneof the product of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

In order to make the objects, technical solutions, and advantages of thepresent disclosure more clear, the present disclosure will be furtherdescribed in detail below with reference to the examples of thedisclosure. It is apparent that the described examples are only a partbut not all of the examples of the present disclosure. All otherexamples obtained by those skilled in the art based on the examples ofthe present disclosure without creative efforts are within theprotection scope of the present disclosure.

Example 1: Preparation of Powder Injection of Donepezil Semi Pamoate

1. Preparation of Medicament Powders Having Different Particle Size

(1) Preparation of Powder 1#

Step 1: 6.6 g of donepezil hydrochloride was dissolved in 250 ml ofpurified water and stirred. 0.34 g of activated carbon was added, andstirred at 40-60° C. for 1-2 hours. The reaction solution was cooled toroom temperature and filtered. The filtrate was retained for use.

Step 2: 3.7 g of disodium pamoate was dissolved in 250 ml of purifiedwater and stirred. 0.18 g of activated carbon was added, and stirred at40-60° C. for 1-2 hours. The reaction solution was cooled to roomtemperature and filtered. The filtrate was retained for use.

Step 3: 0.2 g of donepezil semi pamoate seed crystals (the preparationmethod refers to example 4 of patent WO2013078608) were added into thefiltrate obtained in step 1 to obtain a solution. Then the filtrateobtained in step 2 was slowly and dropwise added into the above solutionat room temperature over 1 hour, slowly stirred for 5-10 hours with ananchor stir bar and filtered. The resulting filter cake was washed withpurified water and dried to finally obtain 9.6 g of solid particles ofdonepezil semi pamoate. The obtained particles have an average particlesize D₅₀ of 90±17 μM as measured by a laser ganulometer.

(2) Preparation of Powder 2#

Step 1 and step 2 are the same as those of powder 1#. Step 3: 0.2 g ofdonepezil semi pamoate seed crystals (the preparation method is the sameas above) were added into the filtrate obtained in step 1 to obtain asolution. Then the filtrate obtained in step 2 was slowly and dropwiseadded into the above solution at 4-10° C. over 1 hour, stirred for 1-2hours at room temperature and filtered. The resulting filter cake waswashed with purified water, dried, and then put into a pulverizerequipped with a 10 mesh sieve one by one to finally obtain 8.1 g ofsolid particles of donepezil semi pamoate. The obtained particles havean average particle size D₅₀ of 42±10 μM as measured by a lasergranulometer.

(3) Preparation of Powder 3#

Step 1 and step 2 are the same as those of powder 1#. Step 3: 0.2 g ofdonepezil semi pamoate seed crystals (the preparation method refers topatent WO2013078608) were added into the filtrate obtained in step 1 toobtain a solution. Then the obtained solution was heated to 50-60° C.The filtrate obtained in step 2 was slowly and dropwise added into theabove solution. After completion of the addition, the reaction solutionwas cooled to room temperature, stirred for 1-2 hours, and filtered. Theresulting filter cake was washed with purified water, dried, and thenput into a sieve pulverizer equipped with a 20 mesh sieve one by one tofinally obtain 8.9 g of solid particles of donepezil semi pamoate (witha yield of 91%). The obtained particles have an average particle sizeD₅₀ of 13±2 μM as measured by a laser granulometer.

(4) Preparation of Powder 4#

The powder 3# prepared above was further subjected to ultrafinepulverization by a jet mill.

Pulverization conditions: the pressure when the powder was injected intothe ultrafine pulverizer was 0.8-1.15 MP; the working pressure of theultrafine pulverizer was 0.7-1.2 MP; and the pulverizing time was 30minutes.

The obtained particles have an average particle size D₅₀ of 3±1 μM asmeasured by a laser granulometer.

(5) Preparation of Powder 5#

The powder 4# prepared above was further subjected to ultrafinepulverization by a jet mill.

Pulverization conditions: the pressure when the powder was injected intothe ultrafine pulverizer was 0.8-1.15 MP: the working pressure of theultrafine pulverizer was 0.7-1.2 MP; and the pulverizing time was 90minutes.

The obtained particles have an average particle size D₅₀ of 0.9±0.4 μMas measured by a laser granulometer.

2. Study on Sterilization Conditions for Powder Injection of DonepezilSemi Pamoate

(1) Assessment of Stability of Medicament Powders Under Dry HeatSterilization Conditions

The powder 3# prepared in Example 1 was placed at 160° C. for 2 hours,and the changes in appearance and weight loss thereof were recorded. Theresults showed that after 2 hours, the powder sample gradually changedfrom light yellow to bright brown, and finally coagulated and melted. Inaddition, a weight loss of about 5.14% was observed. These resultsindicate that donepezil semi pamoate powder cannot tolerate the dry heatsterilization condition of 160° C.

(2) Assessment of Stability of Medicament Powders Under Electron Beam(E-Beam) Irradiation Sterilization Conditions

The powder 3# prepared in Example 1 was dispensed into a 6 mlborosilicate glass container with pyrogens removed, and then irradiatedwith different surface irradiation doses of 20 kGy, 30 kGy, 40 kGy, 50kGy or 60 kGy respectively. Then an acceleration stability study wasperformed by placing the powder bottles at 40° C. under a relativehumidity of 75% for storage. The tests were performed by sampling attime points of 1 month, 2 months, 3 months, and 6 months aftersterilization, respectively.

The test results show that the medicament powders can be stored for afurther extended period under the acceleration stability condition aftersterilization by E-beam irradiation with the sterilization dose of 60kGy, and remain stable, with total impurities of no more than 0.3% andunknown impurities of no more than 0.1%. There were no significantchanges in key physicochemical properties such as appearance,identification, impurities, water content and particle size distributionduring the acceleration test. Therefore, it can be confirmed that E-beamsterilization with a sterilization dose of 60 kGy or less does notadversely affect the basic properties of the medicament.

For the above medicament powders, the best sterilization method isirradiation sterilization, including γ-ray electron beam irradiation andmicrowave irradiation.

Example 2: Appearance and Fluidity Test of Powder Injection of DonepezilSemi Pamoate

The angle of repose is a common index for evaluating the fluidity of drypowder. When measuring the angle of repose, the funnel is fixed at asuitable height H. The dry powder prepared in Example 1 was placed in afunnel and naturally leaked to form a pile until tip of the cone almostcontacts the outlet of the funnel. Then, the radius r of the bottomsurface of the cone was measured, and the angle of repose is arctg(H/r).

The appearance of each of the medicament powders prepared in Example 1was observed and the angle of repose was measured, as shown in Table 1:

TABLE 1 Samples Appearance observed Angle of repose (°) Powder 1#Homogeneous solid particles 28 ± 4 Powder 2# Homogeneous solid particles35 ± 3 Powder 3# Homogeneous solid particles 42 ± 1 Powder 4#Homogeneous solid particles 38 ± 3 Powder 5# Obvious static electricity,and serious 50 ± 4 agglomeration

The general rule deems that powder is very free flowing when its angleof repose is ≤9°; powder is free flowing when its angle of repose is20-29°; powder is general flowing when its angle of repose is 30-39°;and powder is slow flowing when its angle of repose is ≥40°.

It can be seen from the above table that among the five powders withdifferent particle sizes, powder 5# has a poor fluidity, obvious staticelectricity, and serious agglomeration, while powders 1#, 2#, 4# and 3#all have certain fluidity.

Example 3: Study of Formulation for Powder Injection of Donepezil SemiPamoate

1. Suspension Property Study.

The powder 3# prepared in Example 1 was placed in different diluents toformulate a suspension having a concentration of 230 mg/mL to obtaindifferent formulations. The diluents contained 0.75%-1.5% of sodiumcarboxymethyl cellulose (CMC-Na), and 0.05%-0.20% of poloxamer 188 orTween 80. The suspension was then vibrated for 5 minutes and left tostand for 30 minutes. 4 mL of the upper layer, the middle layer and thebottom layer of the suspension were collected and prepared to a 12 mLsolution of respectively to determine the contents of donepezil semipamoate. The relative concentration differences (RCD) between layers ofdonepezil semi pamoate were calculated to evaluate the suspensionproperty of different formulations. The results are shown in Table 2.

TABLE 2 Tween 80 RCD (%) Formulation CMC-Na Poloxamer 188 con- betweenNo. concentration concentration centration layers Formulation 0.75% 0.2% / 1.5 01 Formulation 1.0% 0.2% / 0.5 02 Formulation 1.5% 0.2% / 0.503 Formulation 1.0% 0.05%  / 1.1 04 Formulation 1.0% /  0.2% 1.0 05Formulation 1.0% / 0.05% 1.7 06

As shown in Table 2, the relative standard deviations between layerswere all less than 2% for the content of donepezil semi pamoate withdifferent concentrations of CMC-Na (0.75%-1.5%) and poloxamer 188 orTween 80 (0.05%-0.20%). These results indicate that the aboveformulations have good suspension effect on donepezil semi pamoatepowder.

2. Injectability Study

The diluents containing different concentrations of CMC-Na, poloxamer188 or Tween 80 were prepared, added with powder 2# or powder 3# thatprepared in Example 1 to achieve a concentration of powder 2# or powder3# of 230 mg/mL, and then vibrated for a few minutes until forming auniform suspension. The injectability study was performed by injectingthe suspension using syringes with needles at different sizes. Manualinjectability is divided into 3 levels: +, ++, and +++, which representsimple for injection, moderately difficult for injection, and quitedifficult for injection, respectively. The results are shown in Table 3.

TABLE 3 Poloxamer Formulation Powder CMC-Na 188 Tween 80 Needle type No.No. concentration concentration concentration 22G 21G 20G 18GFormulation Powder 0.75%  0.2% / +++ ++ ++ + 011 3# Formulation Powder1.0% 0.2% / +++ ++ ++ + 021 3# Formulation Powder 1.5% 0.2% / +++ ++++++ ++ 031 3# Formulation Powder 1.0% 0.05%  / +++ ++ ++ + 041 3#Formulation Powder 1.0% /  0.2% +++ ++ ++ ++ 051 3# Formulation Powder1.0% / 0.05% +++ ++ ++ + 061 3# Formulation Powder 1.0% / 0.05% +++ ++++ + 071 2# Formulation Powder 1.0% /  0.1% +++ ++ ++ + 081 2#

Manual test results (Table 3) show that it is quite difficult to injectany one of the suspensions through a 22G needle. When CMC-Na reaches thehighest concentration (L5%), only an 18G needle can be used forinjection with a moderately difficult level. When the formulation samplehas a CMC-Na content of ≤1.0% and a Tween 80 concentration of <2.0%, itcan be injected through an 18G needle.

According to the above comprehensive results of the suspension test andthe injectability study, the optimized dose of CMC-Na ranges from 0.75%to 1.0%.

3. Osmotic Pressure Study

Different amounts of mannitol were added into the above diluents inwhich the concentrations of CMC-Na and poloxamer 188 were fixed as 1%and 0.05%, respectively, and powder 3# was added to formulate asuspension with a concentration of 230 mg/mL. The osmotic pressure ofthe suspension was measured.

The results (Table 4) showed that when the content of mannitol was 4.5%to 5.80%, the osmotic pressure ranges from 285 mOsmol/kg to 330mOsmol/kg.

TABLE 4 Osmotic pressure of diluents containing different amounts ofmannitol Mannitol Osmotic pressure Formulation No. concentration(mOsmol/Kg) Formulation 0111 4.5% 285 Formulation 0211 4.8% 292Formulation 0311 5.0% 310 Formulation 0411 5.2% 318 Formulation 05115.4% 323 Formulation 0611 5.6% 326 Formulation 0711 5.8% 330

Example 4: Preparation of Donepezil Semi Pamoate Injection

7 injection samples of different formulation were prepared according tothe amount of each excipient in the formulation of Table 5. The specificpreparation steps were as follows: 80% of water for injection and thetension agent were mixed and stirred at 50-60° C. After completedissolution, CMC-Na was slowly added, stirred, and added with thewetting agent followed by water for injection, to finally formulate to 3ml dilution solution. The dilution solution was filtered through a 0.22μm filter membrane, and aseptically dispensed into a borosilicate vialwith pyrogens removed. 416 mg of powder injection prepared in Example 1was dissolved in dilution solution to prepare a donepezil semi pamoateinjection when used.

TABLE 5 Samples Amounts Sample Sample Sample Sample Sample Sample SampleComponents 1 2 3 4 5 6 7 Active Powder Powder Powder Powder PowderPowder Powder ingredients 1# 2# 3# 3# 3# 4# 4# Suspending 30 mg 30 mg22.5 mg 30 mg 45 mg 45 mg 22.5 mg agent CMC-Na CMC-Na CMC-Na CMC-NaCMC-Na CMC-Na CMC-Na Tension 144 mg 144 mg 174 mg 135 mg 23 mg 144 mg 15mg agent mannitol mannitol mannitol mannitol NaCl mannitol NaCl Wetting1.5 mg 1.5 mg 6 mg 1.5 mg 3 mg 1.5 mg 1.5 mg agent poloxamer poloxamerTween poloxamer poloxamer Tween Tween 188 188 80 188 188 80 80 Water forUp to Up to Up to Up to Up to Up to Up to injection 3 ml 3 ml 3 ml 3 ml3 ml 3 ml 3 ml

The appearance characteristics, particle size, sedimentation volumeratio, redispersibility, syringeability and other items for the aboveinjections were tested according to the “Pharmacopoeia of the People'sRepublic of China”, 2015 edition. The results show that the indices suchas appearance characteristics, redispersibility, syringeability and soon all meet the requirements; the sedimentation volume ratio is close to1; and the particle size of the powder injection is uniformlydistributed.

Example 5: Test for Stimulation of Donepezil Semi Pamoate Injection onRabbit Muscle

Local reaction of the injection site was observed after a singleinjection of donepezil semi pamoate injection to rabbit muscle topreliminarily evaluate the safety of the formulation.

Methods: 12 New Zealand rabbits of clean grade were randomized into 6groups according to gender and body weight, and 2 animals for each groupwas used for evaluation. Group 1 was a group of vehicle control in whichthe dilution solution of excipients of sample 1 in Example 4 withoutmedicament powder was administered. Groups 2-6 were test groups. Amongthem, powder 1# in Example 1 was administered to the animals in group 2;powder 2# in Example 1 was administered to the animals in group 3;powder 3# in Example 1 was administered to the animals in group 4;powder 4# in Example 1 was administered to the animals in group 5; andpowder 5# in Example 1 was administered to the animals in group 6.During administration, the medicament powders of groups 2-6 weredispersed into the dilution solution of excipients as used for group 1with the medicament dose being adjusted to 85.1 mg (based on donepezil)per animal. Each group of animals was administered by a single injectionvia left quadriceps at a volume of 1 mL per animal.

During the test, the injection site and surrounding tissues werevisually observed for red and swelling, congestion, and otherstimulations. The observation was performed once a day at thecorresponding time after injection.

14 days after the single injection, all test animals were euthanized,and then the left quadriceps of the rabbits were longitudinally incised.The injection site marked during injection was used as baseline, and theadjacent muscles were observed and scored according to the criterialisted in Table 6 below. Finally, comprehensive judgment was made basedon the results of visual observation and histopathological examination.

Observation of Injection Site:

The results of visual observation showed that slight hyperemia wasobserved on day 2 after injection, and erythema was observed on day 2 today 4 after injection at the injection site for one animal in the groupof vehicle control, while the other animal had no obvious symptom at theinjection site.

Red and swelling was observed at the injection site for 2 animals in thetest group 2 on day 2 to day 4 after injection.

Slight red and swelling was observed at the injection site for oneanimal in the test group 4 on day 2 to day 4 after injection, while theanimals in other groups had no obvious symptom at the injection site onday 2 to day 4 after injection.

On day 14 after the single injection, the tested animals in the vehiclecontrol group and the test groups 3 and 5 showed no histopathologicalabnormalities; one of the two animals tested in the test groups 4 and 6only showed slight monocyte infiltration on both sides of skeletalmuscle at the injection site, while the other animal had no obvioussymptom at the injection site; and the tested animals in the test group2 showed moderate monocyte infiltration and slight subcutaneoushemorrhage at the injection site of the muscle, and slight hemorrhageand moderate edema in skeletal muscle.

Muscle Stimulation Evaluation:

The scoring of muscle stimulation response is shown in Table 6. Theexamination results of this experiment are shown in Table 7. It can beseen from Table 7 that the medicament of the test group 2 can causemoderate congestion and edema at the injection site (score=2), while themedicaments of the test groups 3-6 cause a slight hyperemia at theinjection site (score=1).

The above observation results show that the injection of powder 1#prepared in Example 1 has greater stimulation to the muscle at theinjection site, while powder 2#, powder 3#, powder 4# and powder 5#prepared in Example 1 has less stimulation to the muscle afterinjection.

TABLE 6 Stimulation response Score No serious response 0 Slightcongestion, less than 0.5 cm × 1.0 cm 1 Moderate congestion, greaterthan 0.5 cm × 2 1.0 cm, and moderate edema Severe congestion with muscle3 degeneration Necrosis with brown degeneration 4 Massive necrosis 5

TABLE 7 Score on day 14 Group No. Group type Animal No. Gender afterinjection 1 Vehicle 101 M 0 control 102 F 0 2 Powder 1# 201 M 2 202 F 23 Powder 2# 301 M 1 302 F 0 4 Powder 3# 401 M 0 402 F 1 5 Powder 4# 501M 1 502 F 1 6 Powder 5# 601 M 0 602 F 1

CONCLUSIONS

It can be seen from the experiment that powder 14 prepared in Example 1can cause a local stimulation response in the muscle at the injectionsite, while powder 24, powder 34 powder 44 and powder 5# prepared inExample 1 only cause slight stimulation response in the muscle at theinjection site. It follows that powder 2#-5# have relatively highermedicament safety than powder 1#.

It is well known that for long-acting injection suspensions, when thedosage and the excipients are fixed, the larger the particle size ofmedicament powder is, the greater the stimulation to the injection siteafter injection is. However, the present inventors have unexpectedlydiscovered that the medicament stimulation of medicament powder 2#,powder 3# and 4# having large particle sizes is not larger than that ofpowder 5# having a smaller particle size.

The above are only the preferred examples of the present disclosure, andare not intended to limit the present disclosure. Any modifications,equivalents, improvements, and the like made within the spirit andprinciples of the present disclosure should be included within the scopeof the present disclosure.

1. A powder injection of donepezil semi pamoate comprising donepezilsemi pamoate crystals, wherein the donepezil semi pamoate crystals havean average particle size of 0.5-100 μm.
 2. The powder injection ofdonepezil semi pamoate of claim 1, wherein the donepezil semi pamoatecrystals have an angle of repose of 25-46 degrees.
 3. A method forpreparing the powder injection of donepezil semi pamoate of claim 1,comprising: crystallizing donepezil semi pamoate, subjecting to a drypulverization and a sterilization process.
 4. The method for preparingthe powder injection of donepezil semi pamoate of claim 3, comprisingfollowing steps: step 1: dissolving donepezil hydrochloride in purifiedwater, stirring, and filtering to obtain a filtrate; step 2: dissolvingdisodium pamoate in purified water, stirring, and filtering to obtain afiltrate; and step 3: adding donepezil semi pamoate seed crystals to thefiltrate obtained in step 1 to obtain a solution, then dropwise addingthe filtrate obtained in step 2 to the solution, stirring for 1-2 hours,filtering to obtain a filter cake, washing the filter cake with purifiedwater, drying, and performing a dry pulverization and a sterilizationprocess.
 5. The method of claim 4, wherein the sterilization process isa γ-ray irradiation sterilization, an electron beam irradiationsterilization or a microwave irradiation sterilization, and anirradiation dose of the irradiation sterilization is 25 kGy to 60 kGy.6. The method of claim 3, wherein the dry pulverization is performed byusing a sieve pulverizer equipped with a 10-20 mesh sieve.
 7. Acomposition comprising donepezil semi pamoate, wherein the compositioncomprises the powder injection of donepezil semi pamoate of claim 1 orthe powder injection of donepezil semi pamoate obtained by the method ofclaim
 3. 8. The composition of claim 7, wherein the composition furthercomprises a diluent.
 9. The composition of claim 8, wherein the diluentcomprises 0.75%-1.5% of the suspending agent, 4.5%-6% of the tensionagent, and 0.05%-0.2% of the wetting agent.
 10. The composition of claim8, wherein the suspending agent is sodium carboxymethylcellulose, thetension agent is mannitol or sodium chloride, and the wetting agent ispoloxamer 188 or Tween
 80. 11. A method for preparing an injection ofdonepezil semi pamoate, comprising: (1) obtaining the powder injectionof donepezil semi pamoate of claim 1, or the powder injection ofdonepezil semi pamoate obtained by the method of claim 3; and (2) mixingthe powder injection of (1) with a diluent to obtain an injection ofdonepezil semi pamoate, wherein based on total mass of the diluent, thediluent comprises 0.03%-3% of a suspending agent, 3%-6% of a tensionagent, and 0.03%-2% of a wetting agent by mass, and water for injection.12. The method of claim 11, wherein the diluent comprises 0.75%-1.5% ofthe suspending agent, 4.5%-6% of the tension agent, 0.05%-0.2% of thewetting agent and water for injection.
 13. The method of claim 11,wherein the suspending agent is sodium carboxymethylcellulose; thetension agent is mannitol or sodium chloride; and the wetting agent ispoloxamer 188 or Tween
 80. 14. The powder injection of donepezil semipamoate of claim 1, the donepezil semi pamoate crystal have an averageparticle size of 0.5-52 an average particle size of 2-32 or an averageparticle size of 4-15 μm.
 15. The powder injection of donepezil semipamoate of claim 1, wherein the donepezil semi pamoate crystal have anangle of repose of 32-43 degrees.
 16. The method of claim 3, the drypulverization is selected from the group consisting of a sievepulverization, a ball milling pulverization and/or a jet pulverization.17. The composition of claim 7, wherein the powder injection ofdonepezil semi pamoate is present in 13%-24% by mass, based on totalmass of the composition.
 18. The composition of claim 7, wherein basedon total mass of the diluent, the diluent comprises 0.03%-3% of asuspending agent, 3%-6% of a tension agent, and 0.03%-2% of a wettingagent, by mass; the suspending agent is one or more selected from thegroup consisting of methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, alginate, chitosan,glucan, gelatin, polyethylene glycol, polyoxyethylene ether, andpolyoxypropylene ether; the tension agent is one or more selected fromthe group consisting of sodium chloride, dextrose, mannitol, sorbitol,lactose, and sodium sulfate; and the wetting agent is one or moreselected from the group consisting of polysorbate 80, polysorbate 20,poloxamer, lecithin, polyoxyethylene ether, polyoxypropylene ether, andsodium deoxycholate.
 19. The composition of claim 9, the diluentcomprises 0.75%-1.0% of the suspending agent, 4.5%-5.8% of the tensionagent, and 0.05%-0.2% of the wetting agent.
 20. The method of claim 12,wherein the diluent comprises 0.75%-1.0% of the suspending agent,4.5%-5.8% of the tension agent, and 0.05%-0.2% of the wetting agent.